EVALUATION OF MASSIVE PARALLEL SEQUENCING AS A DIAGNOSTIC TOOL FOR FAMILIAL HYPERCHOLESTEROLEMIA

Familial hypercholesterolemia (FH) is one of the most common single gene disorders, which is mostly inherited as an autosomal dominant trait. The physical signs of FH are elevated low den- sity lipoprotein cholesterol (LDL-C), elevated total cholesterol (TC) levels and tendon xantomas. Identification and early treatment of affected individuals is desirable and in lack of physical symp- toms DNA-based diagnosis provides confirmation of diagnosis and enables early patient manage- ment. The majority of FH cases are caused by mutations in four genes (APOB, LADLR, PCSK9, and LDLRAP1). There are commercial kits available for testing of the 20 most common FH caus- ing mutations, but the spectrum of disease-causing mutations is quite diverse in various popula- tions and these tests cover only a minority of disease-causing genetic variants. There is therefore a need to determine the full spectrum of mutations in LDLR, APOB, PCSK9 and LDLRAP1 genes in each population. Here we report mutations found in 16 patients with suspected FH in a sample from the Genome Database of the Latvian population enrolled at the Latvian Centre of Cardiol- ogy. We used the next generation sequencing approach to determine the full spectrum of muta- tions in coding regions of LDLR, APOB, PCSK9, and LDLRAP1. In total we found 22 missense mutations, from which only rs5742904 (Arg3527Gln) in APOB gene had been previously de- scribed as a FH-causing mutation confirming FH in one patient. Possible FH-causing mutations however were identified in the majority of patients. The conclusion is that the most commonly em- ployed commercial mutation panel is not sufficient for diagnosis of FH patients and NGS can help to identify FH-causing mutations in the Latvian population.